Amarin: Amarin (AMRN) shares jumped quite significantly since reporting Reduce-It study results with a market cap around 5B by the time I was writing this article. The purpose of this article is to summarize and compare various CVOT studies that were completed in the past and how they differ from Reduce-It study in terms of efficacy and safety analysis. First a quick review about Amarin. In 2012, Amarin received FDA approval for Marine indication to treat high Triglycerides over 500mg/dl (roughly 5 million population along with competition from Lovaza). Later in 2013, Amarin shares dipped to all time lows after receiving a negative Adcom vote for an additional indication based on Anchor study results; Subsequently, FDA rejected and rescinded Amarin's Anchor spa that dented Amarin's quest for Anchor approval which could had improved company's prescription growth and balance sheet. Since 2013, Amarin struggled to stay afloat and to finish Reduce-It study to completion. My portfolio got a hit when shares touched low to mid 1's as I held on to my shares being confident on FDA approval for Anchor indication. Company was left with only one hope and that was the "Reduce-It Study results". Recently, I bought AMRN shares around 3's keeping in mind my actual loss if Reduce-It study doesn't meet investors and analysts expectations. Personally, due to recent failures with Lovaza and OTC CVOT studies, I wasn't confident if Reduce-It study will succeed. To everyone's surprise, Reduce-It study showed significant reduction in MACE events beating analysts expectations cheering investor community. In a nutshell, primary focus of this article is to discuss Reduce-It study results, its comparisons with other therapies and their subsequent CVOT data's and a quick recap with a cardiologist in reference to Reduce-It study results.
Quick Recap: Reduce-It study enrolled 8179 patients over 4.5 years span and the purpose of this study was to see if use of high dose Vascepa 4gm (pure epa) in combination with a statin will demonstrate reduction in major adverse CV events as compared to placebo. According to Amarin, “Approximatley 25% relative risk reduction, demonstrated to a high degree of statistical significance (p<0.001), in the primary endpoint composite of the first occurrence of MACE, including cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. This result was supported by robust demonstrations of efficacy across multiple secondary endpoints”. Moreover, Vascepa’s safety profile was clean and showed consistent safety profile as was seen in Marine and Anchor trials as well. Amarin's statement Link here. Per Amarin, full data from this study will be presented at AHA meeting on November 10th.
How is Amarin's Reduce-It study data different from other studies including Lovaza, PCSK9 inhibitors, Zetia when used in combination with statin therapies?? How about OTC fish oils?
- Lovaza: Keep in mind, Lovaza is a mixture of EPA and DHA and Vascepa contains primarily eicosapentaenoic acid (EPA, ≥ 96%). DHA is shown to increase LDL. The ASCEND study using 1g dose of Lovaza drug failed to show any significant reduction in CV outcomes as compared to Vascepa that showed 25% reduction. ASCEND study link .The ASCEND trial examined whether fish oil supplements reduce the risk of a CV event in patients with diabetes. Study enrolled 15,480 patients with diabetes. There was no significant difference between the two groups: rate ratio of 0.97 (95% confidence interval 0.87–1.08; p=0.55). Please see the link above for ASCEND study data.
- Zetia (Ezetimibe): A double blind, randomized trial involving 18,144 patients were placed on a combination of simvastatin (40mg) and ezetimibe (10mg) while compared with simvastatin (40mg) and placebo. Link here for study results .Overall, study showed small relative reduction in CV outcomes. Table 2 below from The New England Journal of Medicine shows comparison among two groups.
- PCSK9 inhibitors: Repatha (Amgen) and Praluent (Regeneron) both works to reduce bad cholesterol LDL in the blood. First, they have a moderate benefit with CV outcomes roughly around 15% as compared to Vascepa 25%. "In this dedicated cardiovascular outcomes trial, we found that the addition of evolocumab (Repatha) to statin therapy significantly reduced the risk of cardiovascular events, with a 15% reduction in the risk of the primary composite end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization and a 20% reduction in the risk of the more clinically serious key secondary end point of cardiovascular death, myocardial infarction, or stroke. inhibitors though had no effect on cardiovascular deaths". Please refer to this The New England Journal of Medicine Link here. Secondly, both Repatha and Praluent administered as injections as compared to Vascepa oral pills. Thirdly, another important distinction is the cost difference between PCSK9 inhibitors and Vascepa. Even though, both REGN and AMGN lowered prices on their respective drugs, they are still expensive compared to Vascepa. Insurance companies had already restricted usage of PCSK9 inhibitors. In addition, Vascepa’s safety profile’s advantage over PCSK9 inhibitors is another plus point as compared to PCSK9 inhibitors. Keep in mind PCSK9 inhibitors not clean from safety standpoint as there were cases of possible increased incidence of new onset diabetes in certain patients, Cataracts along with allergic reactions that can be serious. Table 3 shows adverse events associated with Evolocumab therapy Link here.
- OTC fish oils: Traditional fish oil contains both DHA and EPA but in varying proportions. Here is one example, from Amazon.com. If you look closely at the above picture, the label stated, " Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease". Amazon website Link here. Remember, OTC fish oil supplements contain both DHA and EPA and much higher doses needed to consume as well. Questions remain over purity, ingredients and lack of studies are some of the big issues with OTC supplements. As a Pharmacist, I don’t indulge in prescribing OTC supplements as they lack studies and data to prove their big claims that could be easily noticeable from labels.
Cardiologist Interview: Cardiologist works for a local hospital. The interview was conducted over the phone on October 4th 2018.
Do you recommend OTC fish oils and or prescribe Lovaza/vascepa for your patients?
Cardiologist: Yes, I had prescribed both Lovaza and Vascepa depending on which one is covered by the insurance companies for TG over 500. Even though, I haven’t recommended OTC fish oils, but lot of my patients do take OTC fish oils as well.
How do you view Reduce IT study results from cardiology perspective?
Cardiologist: Data looks great though I would be very interested in looking at data as whole next month. By this I mean to see if this data translated into reduction in cardiovascular deaths as well. I need to see the data for secondary endpoints or in subgroup analysis such as diabetes, reduction in TG etc.
How do you incorporate this new data from Reduce-IT study into an existing treatment regimen with statins, PCSK9 inhibitors?
Cardiologist: From cardiology perspective, we had focused on lowering LDL cholesterol aggressively however, new data from Vascepa is opening up a new paradigm in treating TG as well. There were roughly any data out there or any guidelines that showed lowering TG is important as well. However, with recent Reduce-IT study results, from cardiology perspective, this could be a big game changer. I haven’t prescribed PCSK9 inhibitors yet due to insurance barriers and cost associated with these treatments. Though, I will prefer prescribing Vascepa going forward keeping in mind new data, cost and safety. But remember, in clinical medicine patient compliance is very important from drug’s benefit over existing therapies, associated costs and safety. Once Vascepa is approved and covered by insurance carriers for lowering TG in combination with statins, I will prefer it over Lovaza and PCSK9 inhibitors. I’m very excited about treating my patients with Vascepa who are already on statins for LDL reduction.
Would you prescribe Vascepa for statin intolerant patients?
Risks: Raising cash, additional data on November 10th, and Vascepa patents are some of the risk factors associated with Amarin's investment. Shares could be under pressure on November 10th if 25% reduction in MACE events doesn't correlate with reduction in CV deaths as well.
Balance Sheet: Amarin has roughly over 100 million in cash and could do a secondary going forward to raise additional funds; though company's costs associated with R&D spending will drop significantly moving forward after the completion of Reduce-It study.
Conclusion: Reduce-It Study, which was thought to literally fail, impressed wall street and cheers investors with overwhelmingly showing greater than expected reduction in MACE with safety in par with the placebo. Vascepa had shown superior efficacy and safety over PCSK9 inhibitors. Further data on November 10th will provide more insight into Reduce-It study.
Disclosure: I am/we are long AMRN.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.